You are on page 1of 8

International Journal of Surgery 9 (2011) 5e12

Contents lists available at ScienceDirect

International Journal of Surgery


journal homepage: www.theijs.com

Review

Advances in resuscitation strategies


Hasan B. Alam*
Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA

a r t i c l e i n f o a b s t r a c t

Article history: Shock, regardless of etiology is characterized by decreased delivery of oxygen and nutrients to the tissues
Received 4 May 2010 and our interventions are directed towards reversing the cellular ischemia and preventing its conse-
Received in revised form quences. The treatment strategies that are most effective in achieving this goal obviously depend upon
30 July 2010
the different types of shock (hemorrhagic, septic, neurogenic and cardiogenic). This brief review focuses
Accepted 4 September 2010
Available online 15 September 2010
on the two leading etiologies of shock in the surgical patients: bleeding and sepsis, and addresses
a number of new developments that have profoundly altered the treatment paradigms. The emphasis
here is on new research that has dramatically altered our treatment strategies rather than the basic
Keywords:
Hemorrhage
pathophysiology of shock.
Resuscitation Ó 2010 Surgical Associates Ltd. Published by Elsevier Ltd. All rights reserved.
Shock
Sepsis
Bleeding
Blood
Fluids

1. Hemorrhagic shock of early soft thrombus, coagulopathy, and hemodilution.9e12 A


systematic review of 52 animal trials concluded that fluid resuscita-
Exsanguination is one of the leading causes of death following tion appeared to decrease the risk of death in models of severe
trauma1,2 and prompt hemorrhage control along with adequate hemorrhage (RR ¼ 0.48), but increased the risk of death in those with
fluid resuscitation are the key components of early trauma care. less severe hemorrhage (RR ¼ 1.86).13 Furthermore, hypotensive
Similarly, hemorrhage is often encountered in non-trauma patients resuscitation (targeting a lower blood pressure), whenever tested,
as a complication following major surgeries. Despite hemorrhage reduced the risk of death (RR ¼ 0.37). Similarly, a critical review of the
being a common problem, the optimal resuscitative strategy literature failed to find any evidence that pre-hospital advanced life
remains controversial, with vigorous ongoing debates about issues support and improved outcomes in trauma patients.14 In a study that
such as the type of fluid, volume, rate, route of administration, and has generated vigorous debate since its publication in 1994,15 hypo-
endpoints of resuscitation. tensive patients with penetrating torso injury were randomized to
routine fluid resuscitation, or resuscitation was delayed until bleeding
had been surgically controlled. The results of this study demonstrated
1.1. Futility of current methods/adverse effects of aggressive
a survival advantage in the delayed resuscitation group (70% vs. 62%,
resuscitation
p ¼ 0.04). Despite all the controversy, the most impressive finding
remains that withholding fluid resuscitation until hemorrhage
Although it is widely believed that early aggressive fluid resusci-
control did not increase the mortality. The issue of timing and volume
tation is beneficial, clinical and basic science literature fails to provide
of fluid resuscitation in bleeding patients has also been addressed by
conclusive supporting evidence.3e7 As a matter of fact, the basic
The Cochrane Database of Systematic Reviews.16 Only six randomized
rationale for administering intravenous fluids in patients with
clinical trials met the inclusion criteria, and a careful review failed to
ongoing bleeding has been challenged repeatedly for almost a
provide any evidence in support of (or against) early or large volume
century.8 Theoretically, fluid resuscitation in the absence of (or prior
intravenous fluid administration in uncontrolled hemorrhage. Based
to) hemorrhage control can exacerbate bleeding due to the disruption
upon all this information, it is reasonable to conclude that fluid
resuscitation is not a substitute for early hemorrhage control. Low
* Division of Trauma, Emergency Medicine and Surgical Critical
volume, careful resuscitation is reasonable, especially when trying to
Care,
165 Cambridge Street, Suite 810, Boston, MA 02114. Tel.: þ1 617 643 2433. get a dying patient to definitive care. However, early aggressive fluid
E-mail address: hbalam@partners.org. resuscitation, in the absence to hemorrhage control, can’t be justified.

1743-9191/$ e see front matter Ó 2010 Surgical Associates Ltd. Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.ijsu.2010.09.001
6 H.B. Alam / International Journal of Surgery 9 (2011) 5e12

In addition to the impact of resuscitation on bleeding, resusci- products and vasopressors is replacing large volume crystalloid
tation fluids have profound cellular effects. It is now widely infusion. Prompted by the recommendations of some con-
recognized that resuscitation fluids are not completely innocuous, sensus conferences29e32 and due to the unique logistical
and they may actually potentate the cellular injury caused by challenges of the battlefield, the resuscitation strategies being
hemorrhagic shock.17 This concept of “resuscitation injury” has utilized by the US military have changed dramatically: resus-
steadily gained attention since a report by the Institute of Medicine citation is selective, emphasizing low volume and practical
(1999) described in detail the wide spectrum of adverse conse- endpoints, and the use of fluids with logistical advantages (e.g.
quences that can follow resuscitative efforts.18 Historically, the hetastarch) is preferred. The endpoint of resuscitation is not
concept of large volume crystalloids resuscitation was a product of a normal BP, but simply a palpable radial pulse and normal
seminal work by Shires, Moyer, Moss and others during the mental status (in the absence of head injury). Thus, IV fluids are
1960s19e22 and it became common practice during the Vietnam given only selectively, and in much less volumes. Also, early
conflict. Their work suggested that infusion of large volume hemorrhage control is prioritized over aggressive fluid resus-
isotonic crystalloids improved survival, and resuscitation fluids citation. It is difficult to determine the direct impact of these
were needed not only to replace the intra-vascular volume loss, but new strategies on combat casualty outcomes, but is very
also to replenish interstitial deficits. Therefore, these investigators encouraging to note that for the first time since the Crimean
recommended fluid replacement equal to three times the volume of War, the killed in action rate has markedly dropped below the
blood loss (and as high as 8:1 for severe shock). At that time the historic 20% to around 10e14%.33 Hypotensive resuscitation
emphasis was on restoration of intra-vascular and interstitial fluid can be performed by infusing fluids to achieve a desired goal
deficits, without much importance attached to the cytotoxic effects (e.g. target blood pressure), or at a pre-determined fixed rate.
of crystalloid fluids. Isotonic fluids were used widely in Vietnam Pre-clinical data shows that resuscitation to target mean arte-
and it was during this period that the appearance of “shock lung/Da rial pressure (MAP) of 40 mmHg, as opposed to 80 mmHg or
Nang lung” (later termed acute respiratory distress syndrome or higher not only results in decreased blood loss but also in better
ARDS) was first described in soldiers that received massive crys- splanchnic perfusion and tissue oxygenation,34 less acidemia,
talloid resuscitation. Today, ARDS and Multiple Organ Dysfunction hemodilution, thrombocytopenia, and coagulopathy,35 decr-
Syndrome are major causes of delayed mortality in trauma patients. eased apoptotic cell death and tissue injury35,36 and improved
An ever-increasing basic science literature supports the new survival.35,36 However, others have shown in large animal
paradigm that cellular injury is influenced not only by shock, but models that prolonged duration (8 h) of hypotension increases
also by our resuscitation strategies. Today, with the easy availability metabolic stress, tissue hypoxia, and mortality37,38 Still the
of advanced cellular research techniques, we can study the effect of majority of the pre-clinical data favors MAPs between 40 and
resuscitation fluids on the biological systems in much greater 60 mmHg or systolic blood pressure (SBP) between 80 and
detail. Review of the literature suggests that commonly used 90 mmHg. Furthermore, in each of these studies, hypotensive
resuscitation fluids (especially racemic lactated Ringer’s solution) resuscitation with crystalloids was beneficial compared to non-
can exaggerate the post trauma immune activation.23 Therefore, in resuscitated controls. An alternative means of hypotensive
addition to the immediate side effects (worsening of hemorrhage), resuscitation, particularly useful in pre-hospital or austere
delayed complications of fluid resuscitation such as systemic environments where accurate blood pressure measurement
inflammatory response, fluid overload (leading to compartment may not be feasible, is by fluid infusion at a pre-determined rate
syndromes, pulmonary edema etc), anemia, thrombocytopenia, (carefully selected to avoid over resuscitation). In animal
electrolyte/acid-base abnormalities, and cardiac and pulmonary studies, empiric rates of infusion have shown promise. Slow
complications must also be kept in mind.24 Excessive fluid resus- infusion rates with crystalloid have been shown to reduce
citation increases the chances of developing abdominal compart- organ injury,39 cause faster recovery of hemorrhage sup-
ment syndrome in critically ill surgical/trauma, burn, and medical pressed cell mediated immune function40,41 and reduce
patients.25e27 Similarly, in a multicenter study of burn patients, mortality. Overall, the data suggest that hypotensive resusci-
administration of excessive fluids (in excess of 25% of predicted) tation at a fixed rate of 60e80 cc/kg/hour generally maintains
increased the odds of ARDS (OR 1.7), pneumonia (OR 5.7), multiple controlled hypotension to a SBP of 80e90 mmHg (MAP of
organ failure (OR 1.6), blood stream infections (OR 2.9), and death 40e60 mmHg) and that this empiric control of infusion rates is
(OR 5.3).28 beneficial in hemorrhagic shock. Regardless of which approach
is selected (goal directed vs. fixed volume), these pre-clinical
1.2. New development data combined with the clinical evidence15,16 argues strongly
against routine large volume crystalloid resuscitation. The best
It is now being appreciated that resuscitation fluids, like other approach for urban trauma services (short transport times)
drugs, have indication for appropriate use, safe therapeutic doses, appears to be “scoop and run”, where unnecessary field inter-
potential side effects and complications. Despite a paucity of good ventions are avoided and the focus is on fast and efficient
randomized controlled trials (RCT) in this arena, clinical practices transport of the patient to the hospital.42
are rapidly changing. In general, large volume aggressive fluid ii. Hypertonic saline: Another new development is the renewed
resuscitation is becoming increasingly rare, and low volume, interest in hypertonic saline (HTS), not just as a volume
carefully guided resuscitation is more common. A few of these expander but also as an immune modulator. The use of HTS for
issues are discussed in more detail below: resuscitation from hemorrhage was first described in 1980,
when Velesco et. al,43 and DeFelippe et. al,44 reported in
i. Controlled hypotensive resuscitation: In appropriate patients separate studies that hypersomotic sodium chloride rapidly
(e.g. in young victims of penetrating trauma) limiting the rate expands plasma volume after major blood loss. Because of its
and volume of fluid resuscitation prior to hemorrhage control is ability to mobilize interstitial fluids into the vascular space,
rapidly becoming routine practice in large trauma centers. 250 ml of 7.5% saline can achieve results comparable to resus-
Blunt trauma patients with associated head injury are still citation with 2e3 L of 0.9% saline. Since the original reports,
resuscitated to a higher blood pressure, in an attempt to HTS or hypertonic saline combined with dextran (HSD) have
maintain adequate cerebral perfusion, but early use of blood been tested in a number of RCTs, without showing a clear
H.B. Alam / International Journal of Surgery 9 (2011) 5e12 7

survival advantage.45 A meta-analysis evaluated HSD as the conclusions have recently been questioned by a study that
initial treatment for hypovolemic shock by reviewing the suggests that the observed survival differences between
original records from six trials (and 604 subjects).46 Overall patients receiving high and low ratios in the first 24 h may
discharge survival rates were better with HSD resuscitation as simply be due to the fact that survivors live long enough to
compared to conventional resuscitation. HSD resuscitation was receive component therapy (survivor bias).66 Based on the
particularly effective for the sub-group of patients that had battlefield experience, the US Army has instituted a policy of
sustained head injury with a discharge survival rate of 38%, as using a 1:1:1 ratio of PRBC:FFP:platelets in the battlefield for
compared to a rate of 27% for the control group receiving saline. those that meet the criteria for massive resuscitation (expec-
All of these trials had used HTS as a volume expander, but ted to receive >10 units PRBC). However, no well-designed
a more advantageous effect of HTS administration may be the randomized clinical trial has conclusively identified the
attenuation of immune mediated cellular injury. A number of optimal ratios of blood components. Our own institutional
pre-clinical studies have demonstrated that HTS has the policy is to start FFP infusion as early as possible in massively
potential to modulate the immune response, with an overall bleeding patients, by activating Massive Transfusion Protocols
attenuation of immune mediated cellular injury.47e56 A small (MTP) which deliver PRBC:FFP in a ratio of 2:1, and administers
RCT has also shown that initial treatment of trauma patients 6 units of platelets for 10 units PRBC. Despite an ongoing
with HSD inhibits neutrophil adhesion molecule expression debate about the precise ratios, there is general agreement
and favorably modulates the inflammatory response.57 The that the blood products should be administered in the form of
recently established Resuscitation Outcome Consortium an MTP to optimize the processes of care and to improve
(ROC),58 funded by the National Institutes of Health and the US outcomes. The often disorganized process of blood component
Department of Defense initiated two multicenter trials of transfusion in the face of massive hemorrhage benefits from an
hypertonic resuscitation in blunt or penetrating trauma organized and standardized approach that delivers the needed
patients in hypovolemic shock, and severe traumatic brain blood products while avoiding their misuse. Despite these
injury. Both studies were designed to have three randomized obvious attractive features, in a recent review Malone found
groups comparing hypertonic saline/dextran (7.5% saline/6% only 10 such protocols published worldwide.67 The utility of
dextran 70, HSD), hypertonic saline alone (7.5% saline, HTS), MTP (using different ratios of blood components) has already
and normal saline (NS) as the initial resuscitation fluid for the been verified in some case controlled studies. Cotton tested
pre-hospital setting. In addition to the primary endpoints, the effectiveness of a Trauma Exsanguination Protocol (1:2:4
comprehensive data about the immunologic consequences of ratio of platelets:FFP:PRBC) by comparing patients treated
hypertonic resuscitation would also be collected. Unfortu- with the protocol (n ¼ 94 over 18 months) to a cohort of similar
nately, the interim analysis of the data was not favorable, HTD patients admitted during the prior 18 months (n ¼ 117). The
treated patients experienced higher early mortality and no study found that implementation of the protocol reduced 30-
overall benefit compared to the control arm (the full analysis day mortality (51% vs. 66%, p < 0.03), decreased intraoperative
remain unpublished at the time of this writing).59 Despite the crystalloid administration (4.9 L vs. 6.7 L, p ¼ 0.002), and
much lauded laboratory effects of hypertonic saline, this fluid reduced post-operative blood product use (2.8 units PRBCs vs.
has not been the magic bullet hoped for by many researchers. 8.7 units, p < 0.001; 1.7 units FFP vs. 7.9 units, p < 0.001; 0.9
Based upon these clinical data, HTS cannot be recommended units platelets vs. 5.7 units, p < 0.001).68 Dente conducted
for resuscitating trauma patients outside an approved trial. a similar study of an MTP (1:1:1 ratio of platelets:FFP:PRBC), by
Another fluid that remains controversial is albumin. A recent comparing matched patients during one year period before
report [post hoc analysis of patients from the Saline versus and after implementation of protocol (73 protocol, and 84
Albumin Fluid Evaluation (SAFE) study] suggests that albumin matched controls). Implementation of the protocol was found
should be avoided in patients with traumatic brain injury, as it to reduce mortality in the first 24 h (17% with MTP vs. 36% pre-
was associated with a significant increase in mortality.60 MTP, p ¼ 0.008), and at 30 days (34% vs. 55%, p ¼ 0.04), with
iii. Damage control resuscitation: An idea that is gaining a more pronounced impact in the blunt trauma patients.69 This
momentum due to the ongoing war (Iraq and Afghanistan) is study also showed that MTP patients required fewer overall
the concept of hemostatic/damage control resuscitation.61 transfusions of PRBCs and FFP after the first 24 h (2.7 units
Trauma patients are often coagulopathic due to shock and PRBCS vs. 9.3 units, p < 0.0001; 3 units FFP vs. 7.5 units,
tissue injury, and this coagulopathy can be worsened by p < 0.05). While further prospective research is needed to
resuscitation with crystalloids and packed red blood cells specify the exact ratios, there is convincing evidence that
(PRBC), as both are deficient in clotting factors. Observational implementation of standardized protocols for blood compo-
data from civilian trauma centers and the battlefield seem to nent transfusion improves processes of care, reduces overall
suggest that early administration of component therapy con- use of blood components, and improves outcomes.
taining fresh frozen plasma (FFP) and platelets may be bene- iv. Red blood cell substitutes: Although advances in viral
ficial.62,63 A recent retrospective analysis of mixed trauma screening have markedly decreased the risks of infectious
patients requiring surgery and massive transfusion compared transmissions, blood transfusion continues to be associated
FFP:PRBC ratios of 1:1 and 1:4, and showed that only 26% of with numerous serious side effects. In trauma patients, trans-
patients treated with the former ratio died while 87.5% of fusion of red blood cells (especially after prolonged storage) has
patients treated with the latter ratio died (p < 0.0001). In this been shown to disturb the immune system with an early
high risk group with an overall mortality of 55.5%, a 1:4 ratio of immune activation resulting in Systemic Inflammatory
FFP:PRBC increased the relative risk of dying by 18.9 Response Syndrome (SIRS), and a delayed immune suppression
(p < 0.001) when controlling for all other patient variables.64 which predisposes the patients to infections.70 As a matter of
Holcomb’s study of trauma patients at 16 trauma centers fact, transfusion of PRBC remains an independent risk factor for
who required massive transfusion found that an FFP:PRBC increased infections, multiple organ failure, length of hospital
ratio of 1:2 or higher (n ¼ 252) compared to lower ratios stay, and mortality.71e74 This has prompted many researchers
(n ¼ 214) was associated with improved 30-day survival (59.6% to focus their attention on testing alternative oxygen carrying
with high ratio vs. 40.4% with low ratio, p < 0.01).65 These solutions.75 A detailed discussion about the history and the
8 H.B. Alam / International Journal of Surgery 9 (2011) 5e12

development of these products is beyond the scope of this clearly sound, as has been validated by a number of subsequent
article. However, all of these solutions contain some form of studies.83e87 For optimal results, the resuscitation protocol must be
polymerized hemoglobin molecule and are thus labeled as initiated as soon as shock is diagnosed and should not be delayed
hemoglobin-based oxygen carriers (HBOC). A common until admission to the intensive care unit (ICU). Due to venous
problem with the HBOC relates to the scavenging of nitric oxide dilation, and increased capillary leak, most of these patients require
by the free hemoglobin molecule, which results in severe aggressive fluid resuscitation over the first 24 h. During this period,
vasoconstriction, a pro-inflammatory response, and end-organ in addition to ensuring adequate cardiac pre-load (e.g. central
injury. Different formulations differ in the mammalian source venous pressure, pulmonary artery occlusion pressure), parameters
of the hemoglobin and how it is cross-linked, as well as in of tissue perfusion and oxygen delivery (e.g. serum lactate, base
storage and length of shelf-life. Of the HBOCs tested thus far, deficit, urine output, central/mixed venous oxygen saturation,
only Hemopure or HBOC-201 (13 g/dL glutaraldehyde poly- cardiac output) should be carefully monitored. The SAFE study88 has
merized bovine hemoglobin) has remained in contention for shown that albumin and crystalloids are equally safe and effective
possible human use, while other formulations such as Poly- (except for patients with traumatic head injury). Surviving Sepsis
heme (10 g/dL glutaraldehyde polymerized human hemo- Campaign has recently reviewed the literature and published
globin) and HemAssist (10 g/dL diaspirin cross-linked human updated and comprehensive guidelines to guide the resuscitation in
hemoglobin) have fallen out of favor due to negative phase III adult and pediatric patients.89These guidelines also provide
clinical trials. In Sloan’s multicenter randomized clinical trial evidence-based recommendations regarding a wide spectrum of
(RCT) trauma patients in severe hemorrhagic shock received supportive/adjunctive therapies (e.g. glycemic control, steroids,
either 500 ml of saline (n ¼ 53) or HemAssist (n ¼ 58) within vasoactive agents, activated protein C etc).
60 min of presentation. The study found a higher 28-day
mortality in the treatment arm (47% for HemAssist vs. 25% for 2.2. Vasopressors and inotropes
saline, p ¼ 0.015).76 In another multicenter RCT, trauma
patients with severe hypovolemic shock were randomized to Within reasonable limits, blood flow through the tissue beds is
standard of care (n ¼ 62) or HemAssist (n ¼ 53) without any- more important than blood pressure. However, during septic shock
difference in 5- or 28-day mortality.77 Similar findings were autoregulation is not normal and perfusion can become linearly
reported with Polyheme in a subsequent RCT, where trauma dependent on blood pressure. Thus, after the initial fluid resusci-
patients in severe hemorrhagic shock were given either stan- tation (or concomitantly) hypotensive patients may require
dard of care (crystalloid and allogenic blood transfusion, administration of vasopressors to keep the mean arterial pressure
n ¼ 365) or up to 6 units of Polyheme (n ¼ 349). Even after >65 mmHg (which has been shown to preserve tissue perfu-
accounting for numerous protocol violations (17%), there was sion).90,91 Whenever possible, vasopressors should be started after
no mortality benefit in the treatment arm, and a higher rate of providing adequate initial fluid resuscitation. There is no compel-
adverse events (93% for Polyheme vs. 88% for controls, ling, high quality evidence that shows one agent to be superior to
p ¼ 0.041).78 A 2008 meta-analysis of 16 HBOC trials, including another.92 However, Surviving Sepsis Campaign recommends
four trials of trauma patients receiving HemAssist or Polyheme, “norepinephrine or dopamine as the first choice vasopressor agent
raised alarm as patients receiving HBOCs were noted to have to correct hypotension in septic shock (Grade IC)”.89 According to
a significant risk of myocardial infarction (RR, 2.71; 95% CI, them, norephephrine has some attractive features as it increases
1.67e4.40), and mortality (RR, 1.30; 95% CI, 1.05e1.61).79 This MAP (due to vasoconstriction), with little change in heart rate and
meta-analysis also included a single study data from a 2005 some increase in stroke volume. Dopamine is another good choice,
presentation to the U.S. Food and Drug Administration (FDA) on which increases MAP and stroke volume. However, it also increases
HBOC-201 use in surgical patients. HBOC-201 (Hemopure) has heart rate, which may not be desirable. Other choices have some
also been rested in a trauma patient population in South unattractive features. For example epinephrine can cause tachy-
African study but the final results of this trial remain unpub- cardia, decreased splanchnic circulation, and hyperlactemia.
lished.80 HOC 201 has been extensively tested with good results Phenylephrine is a pure vasopressor and is least likely to cause
in animal models (and is approved for veterinary use). It has tachycardia, but it decreases stroke volume. Vasopressin has
also been tested in a large phase III clinical trial (n-688) in recently gained popularity for treating refractory hypotension in
elective orthopedic surgical patients, where use of HBOC-201 septic shock patients, as there is a relative deficiency of this
resulted in less need for PRBC transfusion but a significant hormone in septic shock.93 However, a recent RCT-Vasopressin and
increase in serious adverse events.81 A phase II multicenter trial Septic Shock Trial (VASST), which enrolled 778 patients failed to
in trauma patients entitled Restore Effective Survival in Shock show a survival advantage of vasopressin (0.03 units/min) over
(RESUS) was first submitted to the FDA for approval in 2005. norepinephrine, or a reduction in overall rate of serious adverse
However, after an initial positive response the FDA has events.94 In addition to agents that restore the vascular tone,
repeatedly refused to allow the clinical trial to proceed due to patients with documented or suspected decrease in cardiac func-
concerns about patient safety, despite multiple revisions in the tion (elevated filling pressures and low cardiac output) should be
study protocol. Thus, based upon these current data, the use of given dobutamine as an inotropic agent.89 Administration of these
any HBOCs can’t be endorsed at this time outside of well- agents should be guided by serial measurements of markers of
designed, thoroughly vetted clinical trials. tissue oxygenation, filling pressures and cardiac output, without
making an attempt to achieve supra-normal levels.89
2. Septic shock
2.3. Blood products
2.1. Initial resuscitation
The optimal hemoglobin level has not been determined for
As opposed to hemorrhagic shock, early goal directed resuscita- severely septic patients. Rivers and associates in the early goal
tion has been shown to improve 28-day mortality in a single center, directed therapy trial82 used a target hematocrit of 30% in patients
prospective, RCT.82 Although the exact parameters used to guide who continued to show low central venous oxygen saturation. In
resuscitation in that study have been challenged, the basic concept is a more recent multi-institutional trail of mixed ICU patients (not
H.B. Alam / International Journal of Surgery 9 (2011) 5e12 9

necessarily septic shock patients) hemoglobin levels of 7e9 gm/dL resuscitation or blood transfusion, which makes this approach very
and 10e12 gm/dL were associated with identical outcomes.95 Thus, appealing for the logistically constrained pre-hospital and battlefield
it is reasonable to aim for target hemoglobin between 7 and 9 gm/ environments. It appears that HDAC inhibitors rapidly activate
dL if parameters of tissue oxygenation are adequate. But in cases of nuclear histones as well as numerous cellular proteins to create
depressed tissue oxygenation or in patients with other co-morbid a “pro-survival” phenotype in hemorrhagic and septic shock.105e109
issues (e.g. coronary artery disease, stroke, etc), hemoglobin levels Unpublished data also demonstrate that this approach is very
can be pushed up to 10e12 gm/dL to optimize the tissue oxygen promising for the treatment of traumatic brain injury. A number of
delivery. However, this area remains controversial and evidence- these HDAC inhibitors are currently being tested in phase I and II
based guidelines have been proposed by experts in the field to steer clinical trials (non-traumatic situations). We believe that additional
the transfusion practices in these critically ill patients.96 research in this arena could ultimately lead to a potent pharmaco-
logic adjunct to the treatment of hemorrhagic shock that works by
3. Future directions promoting cell survival during periods of lethal stress.

A number of new and exciting developments in the arena of 3.2. Emergency Preservation and Resuscitation (EPR)
resuscitation research have the potential of radically transforming
clinical care in the near future. Two such areas of research are Up to 80% of trauma deaths occur in the early post-traumatic
discussed here: phase,110 with exsanguination as the dominant etiology.2 Profound
shock from blood loss does not respond well to conventional
3.1. Pharmacologic therapy methods of resuscitation.14 Even when the underlying cause can be
treated and circulation restored, cerebral ischemia lasting 5 min or
Over the years, a number of pharmacologic agents have been longer invariably results in severe brain damage. Often the under-
tested as possible adjuncts to fluid resuscitation. These drugs cover lying injuries are reparable but the patient dies of irreversible shock
a wide spectrum including neuroendocrine agents, calcium channel or severe brain damage. In this setting, strategies to maintain cere-
blockers, ATP-pathway modifiers, prostaglandins, sex steroids, anti- bral and cardiac viability long enough to gain control of hemorrhage
oxidants, anti-inflammatory agents, and immune-modulators. and restore intra-vascular volume could be life saving. This requires
Although there is strong laboratory evidence of their beneficial an entirely new approach to the problem, with emphasis on rapid
effects on tissue perfusion, myocardial contractility, reticulo-endo- total body preservation, repair of injuries during metabolic arrest,
thelial function, cell survival, oxidative injury, and immune activa- and controlled resuscitation: Emergency Preservation and Resusci-
tion, majority of these agents are not yet in clinical use as tation (EPR). Currently, hypothermia is the most effective method for
resuscitative agents. A thorough discussion of the research in this preserving cellular viability during prolonged periods of ischemia.
area is beyond the scope of this article. However, a number of agents Although, no clinical studies have been conducted to test the ther-
aimed at correcting the circulatory and immunologic derangements apeutic benefits of hypothermia in trauma patients, numerous well-
of hemorrhage are worth mentioning as promising pharmacologic designed pre-clinical studies clearly support this concept. It should
adjuncts to resuscitation. Dr. Chaudry’s group has extensively studied be emphasized upfront that induced hypothermia and hypothermia
the role of sex steroids in cytokine responses and neutrophil adhe- secondary to shock are very different entities. Induced hypothermia
sion after hemorrhage; they have proposed estrogen and its analogs is therapeutic in nature whereas hypothermia, seen in severely
as possible beneficial treatments.97 Dr. Coimbra’s group has studied traumatized patients, is a sign of tissue ischemia and failure of
the phosphodiesterase inhibitor, pentoxyfylline, already widely used homeostatic mechanisms to maintain normal body temperature. It
for vascular disease due to its rheologic properties, as a treatment for is clear from the literature that rapid induction of deep/profound
hemorrhage because it reduces neutrophil activation and adhesion.98 hypothermia (<15  C) can improve otherwise dismal outcome after
A Cochrane review recently analyzed data on the opiate antagonist exsanguinating cardiac arrest.111e113 Depending on the degree of
Naloxone which has been studied based on the finding that central hypothermia, good outcomes have been achieved with cardiac
Mu, Epsilon, Kappa, and Delta receptors are activated during arrests of 15, 20, 30 and even 90 min in canine models.114,115
hemorrhagic shock and inhibit Caþþ channels; the data suggested Furthermore, the period of hypothermia can be safely extended to
that further clinical trials are needed to determine if the beneficial 180 min if blood is replaced with organ preservation fluids and low
effects on blood pressure by administration of Naloxone result in any flow cardiopulmonary bypass is continued (as opposed to no flow)
durable improvements in survival.99 A common thread across all of during the arrest period.116 Although ground breaking, the clinical
these potential agents is that they are already in wide clinical use for relevance of these original studies was somewhat limited by reliance
other disorders. Thus, there is great hope that with more clinical on pressure-controlled models of hemorrhagic shock (or no
evidence, these agents whose safety profile has already been tested hemorrhage), an absence of major injuries, and lack of surgical
for various non-trauma indications can be rapidly implemented as interventions. To fill these gaps, our team has utilized clinically
adjuncts to fluid resuscitation. Our group has been studying another realistic large animal models of lethal vascular injuries and soft
group of drugs, also already in wide clinical use for non-trauma tissue trauma to demonstrate that profound hypothermia can be
indications, in animal models of shock. Following hemorrhage, the induced through an emergency thoracotomy approach for total
stress of shock and resuscitation causes an immediate modulation of body protection, with excellent long-term survival and no neuro-
genes and proteins involved in a variety of cellular defense pathways logical damage or significant organ dysfunction.117 In a follow up
through an alteration in their acetylation status.100,101 We hypothe- study, it was established that lethal vascular injuries, above and
sized that histone deacetylase (HDAC) inhibitors such as valproic acid below the diaphragm, can be repaired under hypothermic arrest
(VPA) and suberoylanilide hydroxamic acid (SAHA) may have utility with >75% long-term survival.118 More importantly, it was shown
in the treatment of shock through restoration of normal cellular that hypothermia could be used successfully even after 60 min of
acetylation. We subsequently have shown that HDAC inhibitors normothermic shock (transport time), and that the surviving
rapidly reverse shock induced alterations, restore normal histone animals were not only neurologically intact but also had normal
acetylation, and improve survival in different models of otherwise cognitive functions. Subsequent studies have determined that to
fatal hemorrhagic shock and poly-trauma.102e104 Impressively, this achieve the best results, profound hypothermia must be induced
survival improvement was achieved without conventional fluid rapidly (2  C/min) and reversed at a slower rate (0.5 C/min).119,120
10 H.B. Alam / International Journal of Surgery 9 (2011) 5e12

Induction of hypothermia has been shown to preserve various cell the deleterious immunologic and cellular effects of hemorrhage and
types in the central nervous system, while providing some immu- resuscitation. This is an exciting area of future research but their use
nological advantages, and modulating cell survival pathways.121e123 remains to be validated in robust clinical trials. For now, early and
The optimal depth of hypothermia is 10  C, and decreasing the expeditious control of hemorrhage and modest, goal directed
temperature to ultra-profound levels (5  C) may actually worsen the resuscitation should be the standard of care.
outcome.124 If done appropriately, the safe duration of total body
preservation in poly-trauma is about 60 min,125 and it results in no Conflict of interest
increase in post-operative bleeding or septic complications.126 None.
Technically it is now feasible to induce hypothermia using small,
battery operated, portable equipment (suitable for austere settings Sources of funding
and pre-hospital environment).127 This is associated with excellent
“total body preservation” which may have significant implications National Institutes of Health and US Department of Defense.
not only for treatment of traumatic injuries but also for preserving
organs for transplant.128 Induction of hypothermia not only modu- Ethical approval
lates metabolism but also influences a vide variety of cellular and None.
sub-cellular mechanisms,129 including alteration in transcription of
numerous beneficial genes,130 the down-stream effects of which Acknowledgement
persists long after hypothermia. There is also some data from small
animal models to suggest that similar metabolic arrest (and tissue The author would like to acknowledge research support
preservation) can be achieved with other methods, such as inhaled provided by numerous grants by the Office of Naval Research, US
hydrogen sulfide.131 It may sound futuristic, but the expertise to Army Medical Research and Materiel Command, Defense Advanced
preserve the viability of key organs during repair of otherwise lethal Research Projects Agency, and National Institutes of Health.
injuries is now available,132 and a prospective multi-institutional
clinical trial is scheduled to start later this year.133
References

4. Conclusions 1. Sauaia A, Moore FA, Moore EE, Moser KS, Brennan R, Read RA, et al. Epide-
miology of trauma deaths: a reassessment. J Trauma 1995;38:185e93.
2. Acosta JA, Yang JC, Winchell RJ, Simons RK, Fortlage DA, Hollingsworth-
Treatments of shock have evolved over the last 50 years, but the
Fridlund P, et al. Lethal injuries and time to death in a level I trauma center.
changes over the last decade have been especially dramatic.134e136 J Am Coll Surg 1998;186:528e33.
Based upon contemporary data, early goal directed fluid resuscita- 3. Kaweski SM, Sise MJ, Virgilio RW. The effect of prehospital fluids on survival
tion should be considered the standard of care for septic shock, along in trauma patients. J Trauma 1990;30:1215e8.
4. Turner J, Nicholl J, Webber L, Cox H, Dixon S, Yates D. A randomized controlled
with additional supportive measures as advocated by the Surviving trial of prehospital intravenous fluid replacement therapy in serious trauma.
Sepsis Guidelines.89 The optimal approach for hemorrhagic shock is Health Technol Assess 2000;4:1e57.
not as clear due to a relative paucity of level-1 evidence. However, 5. Greaves MW, Hussein SH. Fluid resuscitation in pre-hospital trauma care:
a consensus view. J R Coll Surg Edinb 2002;47:451e7.
according to my personal opinion the existing literature strongly 6. Dula DJ, Wood GC, Rejmer AR, Starr M, Leicht M. Use of prehospital fluids in
supports some common sense recommendations for the treatment hypotensive blunt trauma patients. Prehosp Emerg Care 2002;6:417e20.
of hemorrhagic shock.137 First, resuscitation is not a substitute for 7. Dutton RP, Mackenzie CF, Scalea TM. Hypotensive resuscitation during active
hemorrhage: impact on in-hospital mortality. J Trauma 2002;52:1141e6.
early hemorrhage control. From the moment of injury, all efforts to 8. Cannon WB, Faser J, Collew EM. The preventive treatment of wound shock.
provide definitive control of hemorrhage as expeditiously as JAm Med Assoc 1918;47:618.
possible must be aggressively pursued. Second, large volume crys- 9. Stern SA, Dronen SC, Birrer P, Wang X. Effect of blood pressure on hemorrhage
volume and survival in a near-fatal hemorrhage model incorporating
talloid resuscitation is deleterious and should be abandoned. Fluid
a vascular injury. Ann Emerg Med 1993;22:155e63.
resuscitation can be safely withheld in patients who have adequate 10. Selby JB, Mathis JE, Berry CF, Hagedorn FN, Illner HP, Shires GT. Effects of
cerebral perfusion (normal mental status in the absence of head isotonic saline solution resuscitation on blood coagulation in uncontrolled
hemorrhage. Surgery 1996;119:528e33.
injury) and a palpable radial pulse, especially if the pre-hospital
11. Sondeen JL, Coppes VG, Holcomb JB. Blood pressure at which rebleeding
transport time is expected to be brief. For situations where the time occurs after resuscitation in swine with aortic injury. J Trauma 2003;54
to definitive care is longer than 15e20 min, initiation of limited (Suppl):S100e7.
volume resuscitation is supported by the literature. Specifically, the 12. Rotondo MF, Schwab CW, McGonigal MD, Phillips 3rd GR, Fruchterman TM,
Kauder DR, et al. ”Damage Control”: an approach for improved survival in
goals should be to maintain either a SBP approximating exsanguinating penetrating abdominal trauma. J Trauma 1993;35:375e83.
80e90 mmHg, or clear mental status (in the absence of head injury) 13. Mapstone J, Roberts I, Evans P. Fluid resuscitation strategies: a systematic
and a palpable radial pulse. At present, it seems that infusion of review of animal trials. J Trauma 2003;55:571e89.
14. Liberman M, Mulder D, Sampalis J. Advanced or basic life support for trauma:
lactated Ringer’s solution (containing only the L-isomer of lactate) is meta-analysis and critical review of the literature. J Trauma 2000;49:584e99.
the best option in the pre-hospital setting, whereas early use of 15. Bickel WH, Wall MJ, Pepe PE, Martin RR, Ginger VF, Allen MK, et al. Immediate
blood products should be strongly considered once the patient versus delayed fluid resuscitation for hypotensive patients with penetrating
torso injuries. N Engl J Med 1994;331:1105e9.
reaches the hospital.18,23,137 While the ideal ratio of blood compo- 16. Kwan I, Bunn F, Roberts I. WHO pre-hospital trauma care steering committee:
nents is under investigation, there is a strong trend in favor of timing and volume of fluid administration for patients with bleeding
starting component therapy early and to administer higher ratios of following trauma. Cochrane Database Syst Rev; 2003 (3):CD002245.
17. Alam HB. An update on fluid resuscitation. Scand J Surg 2006;95:136e45.
FFP and platelets to PRBC. Newer methods for blood component 18. Committee on fluid resuscitation for combat casualties. Fluid resuscitation:
preservation have improved their logistical profile, which may yield state of the science for treating combat casualties and civilian trauma, Report
shelf-stable products for pre-hospital use in the near future.138,139 of the Institute of Medicine. Washington, DC: National Academy Press; 1999.
19. Shires GT, Carrico CJ, Baxter CR, Giesecke AH, Jenkins MT. Principles in
The evidence strongly suggests that applying these ratios through
treatment of severely injured patients. Adv Surg 1970;4:255e324.
an institutional protocol improves delivery of care and outcomes. 20. Shires GT, Coln D, Carrico J, Lightfoot S. Fluid therapy in hemorrhagic shock.
When blood products are not an option, blood substitutes may have Arch Surg 1964;88:688e93.
a role. However, at present, the data on blood substitutes are far too 21. Dillon J, Lunch LJ, Myers R, Butcher HR, Moyer CA. A bioassay of treatment of
hemorrhagic shock. Arch Surg 1966;93:537e55.
mixed to recommend their use outside of trials. Finally, pharmaco- 22. Cervera AL, Moss G. Progressive hypovolumia leading to shock after continous
logic adjuncts to resuscitation may ultimately play a role is reducing hemorrhage and 3:1 crystalloid replacement. Am J Surg 1975;129:670e4.
H.B. Alam / International Journal of Surgery 9 (2011) 5e12 11

23. Alam HB, Rhee P. New developments in fluid resuscitation. Surg Clin North Am 51. Murao Y, Loomis W, Wolf P, Hoyt DB, Junger WG. Effect of hypertonic saline
2007;87:55e72. on its potential to prevent lung tissue damage in a mouse model of hemor-
24. Cotton BA, Guy JS, Morris JA, Abumrad NN. The cellular, metabolic, and rhagic shock. Shock 2003;20:29e34.
systemic consequences of aggressive fluid resuscitation strategies. Shock 52. Murao Y, Hata M, Ohnishi K, Okuchi K, Nakajima Y, Hiasa Y, et al. Hypertonic
2006;26:115e21. saline resuscitation reduces apoptosis and tissue damage of the small intes-
25. Daugherty EL, Hongyan Liang, Taichman D, Hansen-Flaschen J, Fuchs BD. tine in a mouse model of hemorrhagic shock. Shock 2003;20:23e8.
Abdominal compartment syndrome is common in medical intensive care unit 53. Sheppard FR, Moore EE, McLaughlin N, Kelher M, Johnson JL, Silliman CC.
patients receiving large volume resuscitation. J Intensive Care Med Clinically relevant osmolar stress inhibits priming-induced PMN NADPH
2007;22:294e9. oxidase subunit translocation. J Trauma 2005;58:752e7.
26. O’Mara MS, Slater H, Goldfarb IW, Caushaj PF. A prospective, randomized 54. Gonzales RJ, Moore EE, Ciesla DJ, Neto JR, Biffl WL, Silliman CC. Hyper-
evaluation of intra-abdominal pressures with crystalloids and colloid resus- osmolarity abrogates neutrophil cutotoxity provoked by post-shock mesen-
citation in burn patients. J Trauma 2005;58:1011e8. teric lymph. Shock 2002;18:29e32.
27. Balogh Z, Moore FA, Moore EE, Biffl WL. Secondry abdominal compartment 55. Staudenmayer KL, Maier RV, Jelacic S, Bulger EM. Hypertonic saline modulates
syndrome: a potential threat for all trauma clinicians. Injury innate immunity in a model of systemic inflammation. Shock 2005;23:459e63.
2007;38:272e9. 56. Cuschieri J, Gourlay D, Garcia I, Jelacic S, Maier RV. Hypertonic pre-
28. Klein MB, Hayden D, Elson C, Nathens AB, Gamelli RL, Gibran NS, et al. The conditioning inhibits macrophage responsiveness to endotoxin. J Immunol
association between fluid administeration and outcome following major burn. 2002;168:1389e96.
A multicenter study. Ann Surg 2007;245:622e8. 57. Bulger EM, Cuschieri J, Warner K, Maier RV. Hypertonic resuscitation modu-
29. Uniformed Services University of the Health Sciences. Combat Fluid Resusci- lates the inflammatory response in patients with traumatic hemorrhagic
tation. Sponsored by US Office of Naval Research; US Army Medical Research shock. Ann Surg 2007;245:635e41.
and Material Command; Department of Surgery. Bethesda, MD: Department 58. Available at: https://roc.uwctc.org/tiki/tiki-index.php.
of Military and Emergency Medicine; June 18e20, 2001. 59. The NHLBI halts study of concentrated saline for patients with shock due to
30. Defense and Civil Institute of Environmental Medicine. Fluid Resuscitation in lack of survival benefit NIH News [serial on the Internet]. Available at: http://
Combat. Sponsored by Defense R & D Canada, Defense and Civil Institute of www.nih.gov/news/health/mar2009/nhlbi-26.htm; 2009 March 26 [accessed
Environmental Medicine. Toronto, Ontario: Department of Surgery, on 05.04.10].
University of Toronto; and the Office of Naval Research; October 25e26, 60. The SAFE Study Investigators. Saline or albumin for fluid resuscitation in
2001. patients with traumatic brain injury. N Engl J Med 2007;357:874e84.
31. Champion HR. Combat fluid resuscitation: introduction and overview of 61. Holcomb JB, Jenkins D, Rhee P, Johannigman J, Mahoney P, Mehta S, et al.
conferences. J Trauma 2003;54(Suppl.):7e12. Damage control resuscitation: directly addressing the early coagulopathy of
32. Rhee P, Koustova E, Alam HB. Searching for the optimal resuscitation method: trauma. J Trauma 2007;62:307e10.
recommendations for the initial fluid resuscitation of combat casualties. 62. Gonzalez EA, Moore FA, Holcomb JB, Miller CC, Kozar RA, Todd SR, et al. Fresh
J Trauma 2003;54(Suppl.):52e62. frozen plasma should be given earlier to patients receiving massive trans-
33. Gwande A. Casualties of war e military care for the wounded from Iraq and fusion. J Trauma 2007;62:112e9.
Afghanistan. New Engl J Med 2004;351:2471e5. 63. Borgman MA, Spinella PC, Perkins JG, Grathwohl KW, Repine T, Beekley AC,
34. Varela JE, Cohn SM, Diaz I, Giannotti GD, Proctor KG. Splanchnic perfusion et al. The ratio of blood products transfused affects mortality in patients
during delayed, hypotensive, or aggressive fluid resuscitation from uncon- receiving massive transfusions at a combat support hospital. J Trauma
trolled hemorrhage. Shock 2003;20:476e80. 2007;63:805e13.
35. Lu YQ, Cai XJ, Gu LH, Wang Q, Huang WD, Bao DG. Experimental study of 64. Duchesne JC, Hunt JP, Wahl G, Marr AB, Wang YZ, Weintraub SE, et al. Review
controlled fluid resuscitation in the treatment of severe and uncontrolled of current blood transfusions strategies in a mature level i trauma center:
hemorrhagic shock. J Trauma 2007;63:798e804. were we wrong for the last 60 years? J Trauma 2008;65:272e6.
36. Xiao N, Wang XC, Diao YF, Liu R, Tian KL. Effect of initial fluid resuscitation on 65. Holcomb JB, Wade CE, Michalek JE, Chisholm GB, Zarzabal LA, Schreiber MA,
subsequent treatment in uncontrolled hemorrhagic shock in rats. Shock et al. Increased plasma and platelet to red blood cell ratios improves outcome
2004;21:276e80. in 466 massively transfused civilian trauma patients. Ann Surg
37. Skarda DE, Mulier KE, George ME, Beilman GJ. Eight hours of hypotensive 2008;248:447e58.
versus normotensive resuscitation in a porcine model of controlled hemor- 66. Snyder CW, Weinberg JA, McGwin Jr G, Melton SM, George RL, Reiff DA, et al.
rhagic shock. Acad Emerg Med 2008;15:845e52. The relationship of blood product ratio to mortality: survival benefit or
38. Rafie AD, Rath PA, Michell MW, Kirschner RA, Deyo DJ, Prough DS, et al. survival bias? J Trauma 2009;66:358e62.
Hypotensive resuscitation of multiple hemorrhages using crystalloid and 67. Malone DL, Hess JR, Fingerhut A. Massive transfusion practices around the
colloids. Shock 2004;22:262e9. globe and a suggestion for a common massive transfusion protocol. J Trauma
39. Shah KJ, Chiu WC, Scalea TM, Carlson DE. Detrimental effects of rapid fluid 2006;60:S91e6.
resuscitation on hepatocellular function and survival after hemorrhagic shock. 68. Cotton BA, Gunter OL, Isbell J, Au BK, Robertson AM, Morris Jr JA, et al. Damage
Shock 2002;18:242e7. control hematology: the impact of a trauma exsanguination protocol on
40. Knoferl MW, Angele MK, Ayala A, Cioffi WG, Bland KI, Chaudry IH. Do survival and blood product utilization. J Trauma 2008;64:1177e82.
different rates of fluid resuscitation adversely or beneficially influence 69. Dente CJ, Shaz BH, Nicholas JM, Harris RS, Wyrzykowski AD, Patel S, et al.
immune responses after trauma-hemorrhage? J Trauma 1999;46:23e33. Improvements in early mortality and coagulopathy are sustained better in
41. Santibanez-Gallerani AS, Barber AE, Williams SJ, Zhao BSY, Shires GT. patients with blunt trauma after institution of a massive transfusion protocol
Improved survival with early fluid resuscitation following hemorrhagic shock. in a civilian level I trauma center. J Trauma 2009;66:1616e24.
World J Surg 2001;25:592e7. 70. Silliman CC, Moore EE, Johnson JL, Gonzales RJ, Biffl WL. Transfusion of the
42. Haas B, Nathens AB. Pro/con debate: is the scoop and run approach the best injured patient: proceed with caution. Shock 2004;21:291e9.
approach to trauma services organization? Crit Care 2008;12:224e35. 71. Charles A, Shaikh AA, Walters M, Huehl S, Pomerantz R. Blood transfusion in an
43. Velasco IT, Ponieri V, Rocha M, Lopes OU. Hyperosmotic NaCl and severe independent predictor of mortality after blunt trauma. Am Surg 2007;73:1e5.
hemorrhagic shock. Am J Physiol 1980;239:H664. 72. Offner PJ, Moore EE, Biffl WL, Johnson JL, Silliman CC. Increased rate of
44. DeFelippe Jr J, Timoner IJ, Velasco IT, Lopes OU, Rocha-e-Silva M. Treatment of infection associated with transfusion of old blood after severe injury. Arch
refractory hypovolemic shock by 7.5% sodium chloride injections. Lancet Surg 2002;137:711e7.
1980;2:1002. 73. Dunne JR, Malone DL, Tracy JK, Napolitano LM. Allogenic blood transfusion in
45. Bunn F, Roberts I, Tasker R. Hypertonic versus near isotonic crystalloids for the first 24 h after trauma is associated with increased systemic inflammatory
fluid resuscitation in critically ill patients. Cochrane Database Syst Rev 2004;3. response syndrome (SIRS) and death. Surg Infect (Larchmt) 2004;5:395e404.
CD002045. 74. Moore FA, Moore EE, Sauaia A. Blood transfusion. An independent risk factor
46. Wade CE, Kramer GC, Grady JJ, Fabian TC, Younes RN. Efficacy of hypertonic for postinjury multiple organ failure. Arch Surg 1997;132:620e4.
7.5% saline and 6% dextran-70 in treating trauma: a meta-analysis of 75. Moore EE. Blood substitutes: the future is now. J Am Coll Surg 2003;196:1e17.
controlled clinical studies. Surgery 1997;122:609e16. 76. Sloan EP, Koenigsberg M, Gens D, Cipolle M, Runge J, Mallory MN, et al.
47. Junger WG, Coimbra R, Liu FC, Herdon-Remelius C, Junger W, Junger H, et al. Diaspirin cross-linked hemoglobin (dclhb) in the treatment of severe trau-
Hypertonic saline resuscitation: a tool to modulate immune function in matic hemorrhagic shock: a randomized controlled efficacy trial. JAm Med
trauma patients? Shock 1997;8:235e41. Assoc 1999;282:1857e64.
48. Rotstein OD. Novel strategies for immunomodulation after trauma: revisiting 77. Kerner T, Ahlers O, Veit S, Riou B, Saunders M, Pison U. Dcl-hb for trauma
hypertonic saline as a resuscitation strategy for hemorrhagic shock. J Trauma patients with severe hemorrhagic shock: the european “On-scene” Multi-
2000;49:580e3. center study. Intensive Care Med 2003;29:378e85.
49. Bahrami S, Zimmermann K, Szelenyi Z, Hamar J, Scheiflinger F, Redl H, et al. 78. Moore EE, Moore FA, Fabian TC, Bernard AC, Fulda GJ, Hoyt DB, et al. Human
Small volume fluid resuscitation with hypertonic saline prevents inflamma- polymerized hemoglobin for the treatment of hemorrhagic shock when blood
tion but not mortality in a rat model of hemorrhagic shock. Shock is unavailable: the USA multicenter trial. J Am Coll Surg 2009;208:1e13.
2006;25:283e9. 79. Natanson C, Kern SJ, Lurie P, Banks SM, Wolfe SM. Cell-free hemoglobin-based
50. Pascual JL, Ferri LE, Seely AJ, Campisi G, Chaudhury P, Giannias B, et al. blood substitutes and risk of myocardial infarction and death: a meta-anal-
Hypertonic saline resuscitation of hemorrhagic shock diminishes neutrophil ysis. J Am Med Assoc 2008;299:2304e12.
rolling and adherence to endothelium and reduces in vivo vascular leakage. 80. http://clinicaltrials.gov/ct2/show/NCT00301483?term¼HBOC201&rank¼1
Ann Surg 2002;236:634e42. [accessed on 05.03.2010].
12 H.B. Alam / International Journal of Surgery 9 (2011) 5e12

81. Jahr JS, Mackenzie C, Pearce LB, Pitman A, Greenburg AG. HBOC-201 as an 110. Demetriades D, Murray J, Charalambides K, Alo K, Velmahos G, Rhee P, et al.
alternative to blood transfusion: efficacy and safety evaluation in a multi- Trauma fatalities: time and location of hospital deaths. J Am Coll Surg
center phase III trial in elective orthopedic surgery. J Trauma 2004;198:20e6.
2008;64:1484e97. 111. Tisherman SA, Safar P, Radovsky A, Peitzman A, Sterz F, Kuboyama K. Ther-
82. Rivers E, Nguyen B, Havstad S, Ressler J, Muzzin A, Knoblich B, et al, Early apeutic deep hypothermic circulatory arrest in dogs: a resuscitation modality
Goal-Directed Therapy Collaborative Group. Early goal directed therapy in for hemorrhagic shock with "irreparable injury". J Trauma 1990;30:836e47.

the treatment of severe sepsis and septic shock. N Engl J Med 112. Tisherman SA, Safar P, Radovsky A, et al. Profound hypothermia (<10 C)

2001;345:1368e77. compared with deep hypothermia (15 C) improves neurologic outcome in
83. Sebat F, Johnson D, Musthafa AA, Watnik M, Moore S, Henry K, et al. dogs after two hours circulatory arrest induced to enable resuscitative
A multidisciplinary community hospital program for early and rapid resus- surgery. J Trauma 1991;31:1051e62.
citation of shock in nontrauma patients. Chest 2005;127:1729e43. 113. Capone A, Safar P, Radovsky A, Wang YF, Peitzman A, Tisherman SA. Complete
84. Kortgen A, Niederprum P, Bauer M. Implementation of an evidence based recovery after normothermic hemorrhagic shock and profound hypothermic
"standard operating procedure" and outcome in septic shock. Crit Care Med circulatory arrest of 60 min in dogs. J Trauma 1996;40:388e95.
2006;34:943e9. 114. Behringer W, Prueckner S, Kentner R, Tisherman SA, Radovsky A, Clark R, et al.
85. Shapiro NI, Howell MD, Talmor D, Lahey D, Ngo L, Buras J, et al. Imple- Rapid hypothermic aortic flush can achieve survival without brain damage
mentation and outcomes of the Multiple Urgent Sepsis Therapies (MUST) after 30 min cardiac arrest in dogs. Anesthesiology 2000;93:1491e9.
protocol. Crit Care Med 2006;34:1025e32. 115. Behringer W, Safar P, Wu X, et al. Survival without brain damage after clinical
86. Nguyen HB, Corbett SW, Steele R, Banta J, Clark RT, Hayes SR, et al. Imple- death of 60e120 min in dogs using suspended animation by profound
mentation of a bundle of quality indicators for the early management of hypothermia. Crit Care Med 2003;31:1523e31.
severe sepsis and septic shock is associated with decreased mortality. Crit 116. Taylor MJ, Bailes JE, Elrifai AM, Shih SR, Teeple E, Leavitt ML, et al. A new
Care Med 2007;35:1105e12. solution for life without blood: asanguineous low-flow perfusion of a whole
87. Shorr AF, Micek ST, Jackson Jr WL, Kollef MH. Economic implications of an body perfusate during 3 hours of cardiac arrest and profound hypothermia.
evidence-based sepsis protocol: can we improve outcomes and lower costs? Circulation 1995;91:431e44.
Crit Care Med 2007;35:1257e62. 117. Rhee P, Talon E, Eifert S, Anderson D, Stanton K, Koustova E, et al. Induced
88. SAFE Study Investigators. A comparison of albumin and saline for fluid hypothermia during emergency department thoracotomy: an animal model.
resuscitation in the intensive care unit. N Engl J Med 2004;350:2247e56. J Trauma 1999;48:439e49.
89. Dellinger RP, Levy MM, Carlet JM, Bion J, Parker MM, Jaeschke R, et al. 118. Alam HB, Bowyer MW, Koustova E, et al. Learning and memory is preserved
Surviving sepsis campaign: international guidelines for management of following induced asanguineous hyperkalemic hypothermic arrest in a swine
severe sepsis and septic shock: 2008. Crit Care Med 2008;36(1):296e327. model of traumatic exsanguination. Surgery 2002;132:278e88.
90. Hollenberg SM, Ahrens TS, Annane D, Astiz ME, Chalfin DB, Dasta JF, et al. 119. Alam HB, Chen Z, Honma K, Koustova E, Querol RI, Jaskille A, et al. The rate of
Practice parameters for hemodynamic support of sepsis in adult patients: induction of hypothermic arrest determines the outcome in a swine model of
2004 update. Crit Care Med 2004;32:1928e48. lethal hemorrhage. J Trauma 2004;57:961e9.
91. LeDoux D, Astiz ME, Carpati CM, Rackow EC. Effects of perfusion pressure on 120. Alam HB, Rhee P, Honma K, Chen H, Ayuste EC, Lin T, et al. Does the rate of
tissue perfusion in septic shock. Crit Care Med 2000;28:2729e32. rewarming from profound hypothermic arrest influences the outcome in
92. Müllner M, Urbanek B, Havel C, Losert H, Waechter F, Gamper G. Vasopressors a swine model of lethal hemorrhage. J Trauma 2006;60:134e46.
for shock. Cochrane Database Syst Rev; 2004 (3). CD003709. 121. Chen Z, Chen H, Rhee P, Koustova E, Ayuste EC, Honma K, et al. Induction of
93. Russell JA. Vasopressin in vasodilatory and septic shock. Curr Opin Crit Care profound hypothermia modulates the immune/inflammatory response in
2007;13:383e91. a swine model of lethal hemorrhage. Resuscitation 2005;66(2):209e16.
94. Russell JA, Walley KR, Singer J, Gordon AC, Hébert PC, Cooper DJ, et al. Vaso- 122. Alam HB, Chen Z, Ahuja N, Chen H, Conran R, Ayuste EC, et al. Profound
pressin versus norepinephrine infusion in patients with septic shock. N Engl J hypothermia preserves neurons and astrocytes, and protects cognitive func-
Med 2008;358:877e87. tions in a swine model of lethal hemorrhage. J Surg Res 2005;126:172e81.
95. Hébert PC, Wells G, Blajchman MA, Marshall J, Martin C, Pagliarello G, et al. 123. Shuja F, Tabbara M, Li Y, Liu B, Butt MU, Velmahos GC, et al. Profound
A multicenter, randomized, controlled clinical trial of transfusion in critical care. hypothermia decreases cardiac apoptosis through Akt survival pathway. J Am
N Engl J Med 1999;340:409e17. Coll Surg 2009;209(1):89e99.
96. Napolitano LM, Kurek S, Luchette FA, Corwin HL, Barie PS, Tisherman SA, et al. 124. Alam HB, Chen Z, Li Y, Velmahos G, DeMoya M, Keller CE, et al. Profound
Clinical practice guideline: red blood cell transfusion in adult trauma and hypothermia is superior to ultra-profound hypothermia in improving survival
critical care. Crit Care Med 2009;37:3124e57. in a swine model of lethal injuries. Surgery 2006;140:307e14.
97. Yu HP, Chaudry IH. The role of estrogen and receptor agonists in maintaining 125. Alam HB, Duggan M, Li Y, et al. Putting life on hold-for how long? profound
organ function after trauma-hemorrhage. Shock 2009;31:227e37. hypothermic cardiopulmonary bypass in a swine model of complex vascular
98. Deree J, Martins J, de Campos T, Putnam JG, Loomis WH, Wolf P, et al. injuries. J Trauma 2008;64:912e22.
Pentoxifylline attenuates lung injury and modulates transcription factor 126. Sailhamer EA, Chen Z, Ahuja N, Velmahos GC, de Moya M, Rhee P, et al.
activity in hemorrhagic shock. J Surg Res 2007;143:99e108. Profound hypothermic cardiopulmonary bypass facilitates survival without
99. Boeuf B, Poirier V, Gauvin F, Guerguerian AM, Roy C, Farrell CA, et al. Naloxone a high complication rate in a swine model of complex vascular, splenic and
for shock. Cochrane Database Syst Rev; 2003. CD004443. colon injuries. J Am Coll Surg 2007;204:642e53.
100. Lin T, Alam HB, Chen H, Britten-Webb J, Rhee P, Kirkpatrick J, et al. Cardiac 127. Casas F, Alam H, Reeves A, Chen Z, Smith WA. A suspended animation forward
histones are substrates of histone deacetylase activity in hemorrhagic shock lines casualty management system. Artif Organs 2005;29:557e63.
and resuscitation. Surgery 2006;139:365e76. 128. Taylor MJ, Rhee P, Chen Z, Alam HB. Design of preservation solutions for universal
101. Alam HB, Shults C, Ahuja N, Ayuste EC, Chen H, Koustova E, et al. Impact of tissue preservation in vivo: demonstration of efficacy in pre-clinical models of
resuscitation strategies on the acetylation status of cardiac histones in a swine profound hypothermic cardiac arrest. Transplant Proc 2005;37:303e7.
model of hemorrhage. Resuscitation 2008;76:299e310. 129. Kheirbek T, Kochanek AR, Alam HB. Hypothermia in bleeding trauma: a friend
102. Gonzales ER, Chen H, Munuve RM, Mehrani T, Nadel A, Koustova E. Hep- or a foe? Scand J Trauma Resusc Emerg Med 2009 Dec 23;17(1):65 [Epub ahead
atoprotection and lethality rescue by histone deacetylase inhibitor valproic of print].
acid in fatal hemorrhagic shock. J Trauma 2008;65:554e65. 130. Alam HB, Hashmi S, Finkelstein RA, Shuja F, Fukudome EY, Li Y, et al. Alter-
103. Shults C, Sailhamer EA, Li Y, Liu B, Tabbara M, Butt MU, et al. Surviving blood ations in gene expression after induction of profound hypothermia for the
loss without fluid resuscitation. J Trauma 2008;64:629e38. treatment of lethal hemorrhage. J Trauma; 2010 [accepted].
104. Alam H, Shuja F, Butt M, Duggan M, Li Y, Zacharias N, et al. Surviving blood 131. Blackstone E, Morrison M, Roth MB. H2S induces suspended animation-like
loss without blood transfusion in a swine poly-trauma model. Surgery state in mice. Science 2005;308:518.
2009;146:325e33. 132. Fukudome EY, Alam HB. Hypothermia in multisystem trauma. Crit Care Med
105. Sailhamer EA, Li Y, Smith EJ, Shuja F, Shults C, Liu B, et al. Acetylation: a novel 2009;37(Suppl.):S265e72.
method for modulation of the immune response following trauma/hemor- 133. http://clinicaltrials.gov/ct2/show/NCT01042015?term¼EPR&rank¼2
rhage and inflammatory second hit in animals and humans. Surgery [accessed on 05.04.2010].
2008;144:204e16. 134. Velmahos GC, Alam HB. Advances in surgical critical care. Curr Probl Surg
106. Li Y, Yuan Z, Liu B, Sailhamer EA, Shults C, Velmahos GC, et al. Prevention of 2008;45:453e516.
hypoxia-induced neuronal apoptosis through histone deacetylase inhibition. 135. Pepe PE, Dutton RP, Fowler RL. Preoperative resuscitation of the trauma
J Trauma 2008;64:863e70. patient. Curr Opin Anaesthesiol 2008;21:216e21.
107. Li Y, Liu B, Sailhamer EA, Yuan Z, Shults C, Velmahos GC, et al. Cell protective 136. Boldt J. Fluid choice for resuscitation of the trauma patient: a review of the phys-
mechanism of valproic acid in lethal hemorrhagic shock. Surgery iological, pharmacological, and clinical evidence. Can J Anaesth 2004;51:500e13.
2008;144:217e24. 137. Santry H, Alam HB. Fluid resuscitation: past, present and the future. Shock
108. Butt M, Sailhamer E, Li Y, Liu B, Shuja F, Velmahos G, et al. Pharmacologic 2010;33:229e41.
resuscitation: cell protective mechanisms of histone deacetylase inhibition in 138. Spoerke N, Zink K, Cho SD, et al. Lyophalized plasma for resuscitation in
lethal hemorrhagic shock. J Surg Res 2009;156:290e6. a swine model of severe injuries. Arch Surg 2009;144:829e34.
109. Li Y, Liu B, Zhao H, Sailhamer E, Zhang X, Kheirbek T, et al. Protective effect of 139. Shuja F, Shults C, Duggan M, Tabbara M, Butt MU, Fisher TH, et al. Develop-
suberoylanilide hydroxamic acid against LPS-induced septic shock in rodents. ment and testing of freeze dried plasma for the treatment of trauma associ-
Shock 2009;146:325e33. ated coagulopathy. J Trauma 2008;65:975e85. 24.